Abstract:
:WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11-null mice also exhibit early-onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin-releasing hormone production. The CHH/KS-associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Kim YJ,Osborn DP,Lee JY,Araki M,Araki K,Mohun T,Känsäkoski J,Brandstack N,Kim HT,Miralles F,Kim CH,Brown NA,Kim HG,Martinez-Barbera JP,Ataliotis P,Raivio T,Layman LC,Kim SHdoi
10.15252/embr.201744632subject
Has Abstractpub_date
2018-02-01 00:00:00pages
269-289issue
2eissn
1469-221Xissn
1469-3178pii
embr.201744632journal_volume
19pub_type
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